Nondisjunction

Abstract: Somatic alterations in the genome are found in many human tumours. Chromosome rearrangements or base substitutions that activate cellular oncogenes appear to act dominantly. In contrast, recessive alleles apparently contribute to childhood retinoblastoma, as homozygosity (or hemizygosity ) for chromosome 13 is often established in tumours, by either mitotic nondisjunction or recombination. Parallels exist between retinoblastoma and childhood Wilms' tumour (WT). Retinoblastoma is often inherited and accompanied by a deletion of chromosome 13 (band q14), while WT is occasionally associated with aniridia and deletion of chromosome 11 band p13. Most Wilms' tumours are sporadic and not accompanied by these findings, although interstitial deletion of chromosome 11 in tumour, but not normal, cells has been reported. In view of these parallels, we compared constitutional and tumour DNAs from WT patients by using chromosome 11p DNA probes. We report here that although heterozygosity in constitutional DNAs was often preserved in tumour DNAs, one case developed homozygosity for chromosome 11p markers in tumour cells, implying the involvement of chromosomal events in revealing a recessive WT locus. This observation suggests the action of such general mechanisms in a tumour other than retinoblastoma.

Abstract: Mature Drosophila oocytes are arrested in metaphase of the first meiotic division. We have examined microtubule and chromatin reorganization as the meiosis I spindle assembles on maturation using indirect immunofluorescence and laser scanning confocal microscopy. The results suggest that chromatin captures or nucleates microtubules, and that these subsequently form a highly tapered spindle in which the majority of microtubules do not terminate at the poles. Nonexchange homologs separate from each other and move toward opposite poles during spindle assembly. By the time of metaphase arrest, these chromosomes are positioned on opposite half spindles, between the metaphase plate and the spindle poles, with the large nonexchange X chromosomes always closer to the metaphase plate than the smaller nonexchange fourth chromosomes. Nonexchange homologs are therefore oriented on the spindle in the absence of a direct physical linkage, and the spindle position of these chromosomes appears to be determined by size. Loss-of-function mutations at the nod locus, which encodes a kinesin-like protein, cause meiotic loss and nondisjunction of nonexchange chromosomes, but have little or no effect on exchange chromosome segregation. In oocytes lacking functional nod protein, most of the nonexchange chromosomes are ejected from the main chromosomal mass shortly after the nuclear envelope breaks down and microtubules interact with the chromatin. In addition, the nonexchange chromosomes that are associated with spindles in nod/nod oocytes show excessive poleward migration. Based on these observations, and the structural similarity of the nod protein and kinesin, we propose that nonexchange chromosomes are maintained on the half spindle by opposing poleward and anti-poleward forces, and that the nod protein provides the anti-poleward force.

Abstract: Aneuploidy (trisomy or monosomy) is the leading genetic cause of pregnancy loss in humans and results from errors in meiotic chromosome segregation Here, we show that the absence of synaptonemal complex protein 3 (SCP3) promotes aneuploidy in murine oocytes by inducing defective meiotic chromosome segregation The abnormal oocyte karyotype is inherited by embryos, which die in utero at an early stage of development In addition, embryo death in SCP3-deficient females increases with advancing maternal age We found that SCP3 is required for chiasmata formation and for the structural integrity of meiotic chromosomes, suggesting that altered chromosomal structure triggers nondisjunction SCP3 is thus linked to inherited aneuploidy in female germ cells and provides a model system for studying age-dependent degeneration in oocytes